Comparative sequence analyses are an essential component of contemporary genomics research. We are continuing to develop and apply new methods for detecting more complex types of evolutionary sequence constraint, such as lineage-specific constrained sequences or weakly constrained sequences, as well as other types of constraint that might not be reflected in the primary nucleotide sequence. Furthermore, we are utilizing inter-species sequence analyses of functional annotations to identify sequence signatures that might confer function;such approaches are particularly useful for detecting short sequences not evolutionarily constrained in orthologous positions across multiple species, but whose relative position to genes and other features is important. The Section is also developing high-throughput methods to experimentally detect and classify functional genomic sequences. This approach utilizes a flow-cytometry-based selection of GFP-reporter constructs harboring candidate enhancer sequences. Preliminary results are promising and have validated that known sequences with enhancer activity can be detected. Scaling this approach to larger regions of the genome will require the use of new-generation sequencing technologies. Along these lines, the Section is utilizing a next-generation sequencing technology from Illumina/Solexa. We are working both on the wet-lab side to get the machine working optimally, as well as the informatics side, developing approaches to maximize the amount of high-quality sequence data that can be extracted from the raw images produced by the new instrument. We are pursuing a number of applications, including ChIP-Seq, RNA-Seq, and other "tag" based counting experiments, as well as medically-relevant de novo genome sequencing projects that can now be pursued at a dramatically reduced cost. This work will not only enable the above-mentioned research projects in my Section, but also many others in the Institute looking to take advantage of this new technology for their own projects.